Frontotemporal dementia (FTD) is a neurodegenerative disease that accounts for 10-20% of dementia cases under the age of 65 and is typically fatal within the five years of diagnosis. There are currently no effective therapeutics. Single nucleotide polymorphisms (SNPs) in the gene TMEM106B were recently found to be a risk factor in FTLD-TDP, a major neuropathological subset of FTD. The TMEM106B risk genotype is also associated with higher TMEM106B levels, lower plasma progranulin levels, and earlier onset of disease in patients carrying mutations in the progranulin gene. This effect on progranulin is notable, as ~10% of FTLD- TDP is caused by mutations in this neurotrophic growth factor. These disease-associated mutations result in either decreased expression or decreased secretion of progranulin, and thus insufficient progranulin seems to be a major driver of disease. Given the effects of TMEM106B on progranulin, early efforts have been made to learn more TMEM106B, a minimally characterized protein. Preliminary evidence has shown that increased expression of TMEM106B alters the endolysosomal equilibrium of cells as well as the distribution of progranulin, increasing its intracellular levels. The major premise of this proposal is that increased levels of TMEM106B, as associated with the FTLD-TDP risk haplotype, 1) alter and impair endo-lysosomal pathways and functions and 2) that this endolysosomal perturbation impairs progranulin trafficking, resulting in the loss of its neurotrophic effects. In line with this premise, several aims are pursued: 1) To determine the function of TMEM106B in the endolysosomal pathway and elucidate the mechanism by which increased TMEM106B results in endolysosomal disequilibrium 2) To determine the mechanism of TMEM106B's effect on progranulin levels and assess if altered TMEM106B levels affect progranulin's neurotrophic effects. In pursuit of these aims, immunohistochemistry, biochemistry, subcellular fractionation, and survival experiments will be conducted in immortalized cell lines as well as in primary mouse neurons. Elucidation of the normal function of TMEM106B and its dysfunction in disease could yield important therapeutic targets that would focus on restoring progranulin's neurotrophic effects.